1. Technical Field
The present invention provides a process for sterilizing a pharmaceutical preparation such as a dispersion of small particles or droplets of a pharmaceutically active compound using high pressure terminal sterilization techniques and products therefrom.
2. Background of the Invention
There is an ever increasing number of organic compounds being formulated for therapeutic or diagnostic effects that are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges to delivering them by administrative routes commonly used by medical personnel. One potential solution to this challenge is to produce small particles of the insoluble drug candidate by preparing micro- or nanoparticulate dispersions therefrom. Benefits derived from such a formulation can include higher loading, reduced toxicity, improved drug saturation solubility and/or dissolution rate, improved efficacy, and enhanced drug stability.
In this way, drugs that were previously unable to be formulated in an aqueous based system can be made suitable for various routes of administration. Preparations of small particle dispersions of water insoluble drugs may be delivered via intraveneous, oral, pulmonary, topical, intrathecal, ophthalmic, nasal, buccal, rectal, vaginal, and transdermal routes. The optimum size range for these dispersions generally depends on the specific route, particle characteristics, and other factors, e.g., in intraveneous administration it is desirable to have a particle size of less than about 7 um. Particles must be in this size range and unaggregated to safely pass through capillaries without causing emboli (Allen et al., 1987; Davis and Taube, 1978; Schroeder et al., 1978; Yokel et al., 1981).
Depending on the route of administration and other factors, these small particle dispersions have to meet certain requirements of sterility. One useful sterilization method is conventional terminal autoclaving of small particle dispersions at 121° C. It is well known that pharmaceutical suspensions are protected from particle growth and/or aggregation during storage at normal temperatures by the presence of surfactants in the formulations. Even in the presence of these stabilizing surfactants, however, small particle suspensions are often quite heat-sensitive and cannot tolerate terminal autoclaving. The pharmaceutically active ingredient, surfactants, and the drug/surfactant assembly have to remain both physically and chemically stable during the entire sterilization cycle at 121° C. The chemical suspectibility of small particle dispersions to terminal autoclaving is known to be both a function of sterilization time and temperature. Methods for curtailing chemical instability generally involve high-temperature short-time sterilization processes. In this case, the preservation of the heat-labile formulation and destruction of microorganisms is based on the differences in rates of chemical degradation and inactivation, respectively. A significant challenge in this process is obtaining rapid enough heat transfer such that a uniform temperature exists throughout the product during the very short time of exposure.
The physical stability of the drug/surfactant assembly is also often difficult to maintain. The small particles frequently aggregate, grow, and/or degrade in the presence of the heat, rendering the final dispersion unusable. In addition, the surfactant assembly may dissociate from the pharmaceutically active compound in an irreversible fashion. For example, one mechanism of aggregation or coalescence of solid submicron particle dispersions can be directly related to precipitation of the stabilizing surfactant during the sterilization process, at temperatures above the surfactant's cloud point. The term “cloud point” refers to separation of an isotropic surfactant solution into one surfactant-rich and one surfactant-poor phase. At such temperatures, the surfactant often dissociates from the particle, causing the unprotected particles to aggregate and/or grow. Consequently, a number of patents (e.g., U.S. Pat. No. 5,298,262, U.S. Pat. No. 5,346,702, U.S. Pat. No. 5,470,583, U.S. Pat. No. 5,336,507) disclose using ionic and non-ionic cloud point modifiers to stabilize particle suspension during autoclaving. These modifiers raise the cloud point of the surfactant above 121° C., preventing the disassociation of the surfactant from the drug particle, and subsequently stabilize the particles from growth during terminal sterilization.
U.S. Pat. No. 6,267,989 also discloses that an optimal size range is most important to minimize growth and instability during autoclaving. The '989 patent reports that the highest stability is exhibited when at least 50% of the surfactant-stabilized drug particles have a weight average particle size between 150-350 nm.
Therefore, there is a continued need to develop new and improved processes for terminal sterilization of small particle dispersions in the pharmaceutical field, and the present invention addresses these needs.
Systems and solutions other that particulate dispersions often require sterilization prior to use. Examples include dissolved pharmaceutical solutions, solutions for renal application (e.g., peritoneal dialysis) and other forms of pharmaceutical preparations such as lipid emulsions. Other examples include medical device disposables, such as pharmaceutical-containing bags (often made of plasticized PVC or other plastics), blood-containing bags, dialyzers, systems for use on automated devices (e.g., blood separation devices, infusion pumps, etc.) Such systems may be sensitive to traditional sterilization techniques such as gamma sterilization, ETO sterilization or autoclaving. For example, glucose-containing solutions are subject to glucose breakdown or aggregation following traditional sterilization techniques. A need also exists, therefore, for the provision of improved sterilization techniques that provide adequate sterilization with little to no compromise of the system sterilized.